Mechanisms of TGF- 1–Induced Intimal Growth Plasminogen-Independent Activities of Plasminogen Activator Inhibitor-1 and Heterogeneous Origin of Intimal Cells

Transforming growth factor (TGF)1 is a potent stimulator of intimal growth. We showed previously that TGF1 stimulates intimal growth through early upregulation of plasminogen activator inhibitor-1 (PAI-1) and, subsequently, PAI-1–dependent increases in cell migration and matrix accumulation. We also showed that PAI-1 negatively regulates TGF1 expression in the artery wall. Here we use plasminogen-deficient mice to test whether TGF1–stimulated, PAI-1–dependent intimal growth and PAI-1 suppression of TGF1 expression are mediated through inhibition of plasminogen activation by PAI-1. We also use lineage tracing to investigate the origin of cells in TGF1–induced intimas. Surprisingly, both TGF1–induced, PAI-1–dependent intimal growth and PAI-1 suppression of TGF1 expression are independent of plasminogen. Moreover, approximately 50% of cells that migrate into the intima of TGF1–overexpressing arteries carry a smooth muscle lineage marker, 1% carry a bone marrow lineage marker, and the remaining cells carry neither marker. Therefore, PAI-1 stimulates intimal growth and suppresses TGF1 expression through activities other than inhibition of plasminogen activation. In addition, contrary to widely held models, our results do not support a role for plasmin (or thrombospondin) in TGF1 activation in the artery wall. Further identification of the molecular targets through which PAI-1 stimulates intimal formation and suppresses TGF1 expression in the artery wall may reveal new approaches for inhibiting intimal formation. Our studies also discount bone marrow as an important source from which TGF1 recruits intimal cells and suggest instead that TGF1 induces substantial cell migration either from the adventitia or from an extravascular, but nonhematopoietic source. (Circ Res. 2007;100:1300-1307.)